Melphalan at a dose of 200 mg/m2 is standard conditioning prior to autologous hematopoietic stem cell transplantation for multiple myeloma, but a dose of 140 mg/m2 is often used in clinical practice in patients perceived to be at risk of excess toxicity. To determine whether melphalan 200 mg/m2 and melphalan 140 mg/m2 are equally effective and tolerable in clinically relevant patient subgroups we analyzed 1964 first single autologous transplantation episodes using a series of Cox proportional-hazards models. Overall survival, progression-free survival, cumulative incidence of relapse, non-relapse mortality, hematopoietic recovery and second primary malignancy rates were not significantly different between the melphalan 140 mg/m2 (n=245) and melphalan 200 mg/m2 (n=1719) groups. Multivariable subgroup analysis showed that disease status at transplantation interacted with overall survival, progression-free survival, and cumulative incidence of relapse, with a significant advantage associated with melphalan 200 mg/m2 in patients transplanted in less than partial response (adjusted hazard ratios for melphalan 200 mg/m2versus melphalan 140 mg/m2: 0.5, 0.54, and 0.56). In contrast, transplantation in very good partial or complete response significantly favored melphalan 140 mg/m2 for overall survival (adjusted hazard ratio: 2.02). Age, renal function, prior proteasome inhibitor treatment, gender, or Karnofsky score did not interact with overall/progression-free survival or relapse rate in the melphalan dose groups. There were no significant survival or relapse rate differences between melphalan 200 mg/m2 and melphalan 140 mg/m2 patients with high-risk or standard-risk chromosomal abnormalities. In conclusion, remission status at the time of transplantation may favor the use of melphalan 200 mg/m2 or melphalan 140 mg/m2 for key transplant outcomes (NCT01362972).

Charles University Hospital Prague Czech Republic

CHU de Lille LIRIC INSERM U995 France

CHU Nantes France

Department of Biology Tor Vergata University of Rome Italy

Department of Medicine Imperial College London UK

EBMT Data Office Leiden the Netherlands

Fundeni Clinical Institute Bucharest Romania

George Papanicolaou General Hospital Thessaloniki Greece

Heinrich Heine Universität Düsseldorf Germany

Hôpital Saint Antoine Paris France

Institut Paoli Calmettes Marseille France

Kuopio University Hospital Finland

Medical University Warsaw Poland

Nottingham University UK

Queens University of Belfast Northern Ireland

Radboud University Medical Centre Nijmegen the Netherlands

Skåne University Hospital Lund Sweden

St James's Hospital Trinity College Dublin Ireland

Umeå University Hospital Sweden

University Hospital Brno Czech Republic

University Hospital Hamburg Eppendorf Hamburg Germany

University of Cologne Germany

University of Heidelberg Germany

Zobrazit více v PubMed

Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med. 1996;335(2):91–97. PubMed

Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348(19):1875–1883. PubMed

Palumbo A, Cavallo F, Gay F, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014;371(10):895–905. PubMed

Gay F, Oliva S, Petrucci MT, et al. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015;16(16):1617–1629. PubMed

Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376(14):1311–1320. PubMed PMC

Gay F, Oliva S, Petrucci MT, et al. Autologous transplant vs oral chemotherapy and lenalidomide in newly diagnosed young myeloma patients: a pooled analysis. Leukemia. 2017;31(8):1727–1734. PubMed

Auner HW, Szydlo R, Hoek J, et al. Trends in autologous hematopoietic cell transplantation for multiple myeloma in Europe: increased use and improved outcomes in elderly patients in recent years. Bone Marrow Transplant. 2015;50(2):209–215. PubMed

Costa LJ, Zhang MJ, Zhong X, et al. Trends in utilization and outcomes of autologous transplantation as early therapy for multiple myeloma. Biol Blood Marrow Transplant. 2013;19(11):1615–1624. PubMed PMC

Facon T, Mary JY, Hulin C, et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet. 2007;370(9594):1209–1218. PubMed

Palumbo A, Bringhen S, Petrucci MT, et al. Intermediate-dose melphalan improves survival of myeloma patients aged 50 to 70: results of a randomized controlled trial. Blood. 2004;104(10):3052–3057. PubMed

Lahuerta JJ, Mateos MV, Martinez-Lopez J, et al. Busulfan 12 mg/kg plus melphalan 140 mg/m2 versus melphalan 200 mg/m2 as conditioning regimens for autologous transplantation in newly diagnosed multiple myeloma patients included in the PETHE-MA/GEM2000 study. Haematologica. 2010;95(11):1913–1920. PubMed PMC

Moreau P, Facon T, Attal M, et al. Comparison of 200 mg/m(2) melphalan and 8 Gy total body irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myelome 9502 randomized trial. Blood. 2002;99(3):731–735. PubMed

Palumbo A, Bringhen S, Bruno B, et al. Melphalan 200 mg/m(2) versus melphalan 100 mg/m(2) in newly diagnosed myeloma patients: a prospective, multicenter phase 3 study. Blood. 2010;115(10):1873–1879. PubMed

Jagannath S, Vesole DH, Glenn L, Crowley J, Barlogie B. Low-risk intensive therapy for multiple myeloma with combined autologous bone marrow and blood stem cell support. Blood. 1992;80(7):1666–1672. PubMed

Shah N, Callander N, Ganguly S, et al. Hematopoietic stem cell transplantation for multiple myeloma: guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2015;21(7):1155–1166. PubMed

Giralt S. 200 mg/m(2) melphalan--the gold standard for multiple myeloma. Nat Rev Clin Oncol. 2010;7(9):490–491. PubMed

Badros A, Barlogie B, Siegel E, et al. Autologous stem cell transplantation in elderly multiple myeloma patients over the age of 70 years. Br J Haematol. 2001;114(3):600–607. PubMed

Badros A, Barlogie B, Siegel E, et al. Results of autologous stem cell transplant in multiple myeloma patients with renal failure. Br J Haematol. 2001;114(4):822–829. PubMed

Sweiss K, Patel S, Culos K, Oh A, Rondelli D, Patel P. Melphalan 200 mg/m2 in patients with renal impairment is associated with increased short-term toxicity but improved response and longer treatment-free survival. Bone Marrow Transplant. 2016;51(10):1337–1341. PubMed

Katragadda L, McCullough LM, Dai Y, et al. Effect of melphalan 140 mg/m(2) vs 200 mg/m(2) on toxicities and outcomes in multiple myeloma patients undergoing single autologous stem cell transplantation-a single center experience. Clin Transplant. 2016;30(8):894–900. PubMed

Dhakal B, Nelson A, Guru Murthy GS, et al. Autologous hematopoietic cell transplantation in patients with multiple myeloma: effect of age. Clin Lymphoma Myeloma Leuk. 2017;17(3):165–172. PubMed

Gertz MA, Lacy MQ, Dispenzieri A, et al. Impact of age and serum creatinine value on outcome after autologous blood stem cell transplantation for patients with multiple myeloma. Bone Marrow Transplant. 2007;39(10):605–611. PubMed

Kumar SK, Dingli D, Lacy MQ, et al. Autologous stem cell transplantation in patients of 70 years and older with multiple myeloma: results from a matched pair analysis. Am J Hematol. 2008;83(8):614–617. PubMed

Garderet L, Beohou E, Caillot D, et al. Upfront autologous stem cell transplantation for newly diagnosed elderly multiple myeloma patients: a prospective multicenter study. Haematologica. 2016;101(11):1390–1397. PubMed PMC

Dimopoulos MA, Terpos E, Chanan-Khan A, et al. Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. J Clin Oncol. 2010;28(33):4976–4984. PubMed

Muchtar E, Dingli D, Kumar S, et al. Autologous stem cell transplant for multiple myeloma patients 70 years or older. Bone Marrow Transplant. 2016;51(11):1449–1455. PubMed

Moreau P, San Miguel J, Sonneveld P, et al. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl_4):iv52–iv61. PubMed

Cavo M, Petrucci MT, Di Raimondo F, et al. Upfront single versus double autologous stem cell transplantation for newly diagnosed multiple myeloma: an intergroup, multicenter, phase III study of the European Myeloma Network (EMN02/HO95 MM Trial). Blood. 2016;128(22):991.

Nath CE, Shaw PJ, Trotman J, et al. Population pharmacokinetics of melphalan in patients with multiple myeloma undergoing high dose therapy. Br J Clin Pharmacol. 2010;69(5):484–497. PubMed PMC

Shaw PJ, Nath CE, Lazarus HM. Not too little, not too much-just right! (better ways to give high dose melphalan). Bone Marrow Transplant. 2014;49(12):1457–1465. PubMed

Nath CE, Trotman J, Tiley C, et al. High melphalan exposure is associated with improved overall survival in myeloma patients receiving high dose melphalan and autologous transplantation. Br J Clin Pharmacol. 2016;82(1):149–159. PubMed PMC

Merz M, Neben K, Raab MS, et al. Autologous stem cell transplantation for elderly patients with newly diagnosed multiple myeloma in the era of novel agents. Ann Oncol. 2014;25(1):189–195. PubMed

Bashir Q, Shah N, Parmar S, et al. Feasibility of autologous hematopoietic stem cell transplant in patients aged >/=70 years with multiple myeloma. Leuk Lymphoma. 2012;53(1):118–122. PubMed

Auner HW, Garderet L, Kroger N. Autologous haematopoietic cell transplantation in elderly patients with multiple myeloma. Br J Haematol. 2015;171(4):453–462. PubMed

Straka C, Liebisch P, Salwender H, et al. Autotransplant with and without induction chemotherapy in older multiple myeloma patients: long-term outcome of a randomized trial. Haematologica. 2016;101(11):1398–1406. PubMed PMC

Engelhardt M, Ihorst G, Caers J, Gunther A, Wasch R. Autotransplants in older multiple myeloma patients: hype or hope in the era of novel agents? Haematologica. 2016;101(11):1276–1278. PubMed PMC

Zweegman S, Engelhardt M, Larocca A, EHA SWG on “Aging and Hematology”. Elderly patients with multiple myeloma: towards a frailty approach? Curr Opin Oncol. 2017;29(5):315–321. PubMed

Engelhardt M, Domm AS, Dold SM, et al. A concise revised Myeloma Comorbidity Index as a valid prognostic instrument in a large cohort of 801 multiple myeloma patients. Haematologica. 2017;102(5):910–921. PubMed PMC

Bruno B, Auner HW, Gahrton G, et al. Stem cell transplantation in multiple myeloma and other plasma cell disorders (report from an EBMT preceptorship meeting). Leuk Lymphoma. 2016;57(6):1256–1268. PubMed

Palumbo A, Bringhen S, Mateos MV, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood. 2015;125(13):2068–2074. PubMed PMC

Roussel M, Moreau P, Huynh A, et al. Bortezomib and high-dose melphalan as conditioning regimen before autologous stem cell transplantation in patients with de novo multiple myeloma: a phase 2 study of the Intergroupe Francophone du Myelome (IFM). Blood. 2010;115(1):32–37. PubMed

Blanes M, Lahuerta JJ, Gonzalez JD, et al. Intravenous busulfan and melphalan as a conditioning regimen for autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: a matched comparison to a melphalan-only approach. Biol Blood Marrow Transplant. 2013;19(1):69–74. PubMed

Rodriguez TE, Hari P, Stiff PJ, Smith SE, Sterrenberg D, Vesole DH. Busulfan, melphalan, and bortezomib versus high-dose melphalan as a conditioning regimen for autologous hematopoietic stem cell transplantation in multiple myeloma. Biol Blood Marrow Transplant. 2016;22(8):1391–1396. PubMed PMC

Nieto Y, Valdez BC, Pingali SR, et al. High-dose gemcitabine, busulfan, and melphalan for autologous stem-cell transplant in patients with relapsed or refractory myeloma: a phase 2 trial and matched-pair comparison with melphalan. Lancet Haematol. 2017;4(6):e283–e292. PubMed PMC

Morgan GJ, Rasche L. Haematological cancer: Where are we now with the treatment of multiple myeloma? Nat Rev Clin Oncol. 2017;14(8):461–462. PubMed

An early post-transplant relapse prediction score in multiple myeloma: a large cohort study from the chronic malignancies working party of EBMT

Complications of Autologous Stem Cell Transplantation in Multiple Myeloma: Results from the CALM Study

Zobrazit více v PubMed

ClinicalTrials.gov
NCT01362972